Abstract | OBJECTIVE: METHODS: Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. RESULTS: Forty-six patients were treated across nine dose levels (12.5-750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. CONCLUSIONS:
VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.
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Authors | Suzanne F Jones, Lillian L Siu, Johanna C Bendell, James M Cleary, Albiruni R A Razak, Jeffrey R Infante, Shuchi S Pandya, Philippe L Bedard, Kristen J Pierce, Brett Houk, W Gregory Roberts, S Martin Shreeve, Geoffrey I Shapiro |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 33
Issue 5
Pg. 1100-7
(10 2015)
ISSN: 1573-0646 [Electronic] United States |
PMID | 26334219
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Benzamides
- Organic Chemicals
- Pyrazines
- Sulfonamides
- defactinib
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Topics |
- Adult
- Aged
- Antineoplastic Agents
(administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
- Area Under Curve
- Benzamides
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Female
- Food-Drug Interactions
- Half-Life
- Humans
- Male
- Maximum Tolerated Dose
- Middle Aged
- Neoplasms
(drug therapy)
- Organic Chemicals
(administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
- Pyrazines
- Sulfonamides
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